Asthma has been regarded as a complex syndrome occurring in the airways, which shows various disorders such as airflow obstruction, acute or chronic inflammation, airway hyper-responsiveness (AHR) and structural remodeling (Kumar R. K. Pharmacol. Ther., 91, pp 93-104, 2001).
Allergic inflammation occurring in the airways has been reported to play a critical role in asthma development and the number of patients suffering from allergic asthma has been increased to about 10% of the population in the world recently. It has been reported that the number has been reached to seventeen million in America and the market scale of the medication for allergic asthma has been enlarged to 640 billion $ in America till now.
Asthma can be classified into two types, i.e., extrinsic asthma and intrinsic asthma. Extrinsic asthma caused by the exposure of antigen such as house dust mite Dermatophagoides as a main antigen, pollen, epithelium of animal, fungi etc shows positive reaction in skin test or bronchial provocation test against the antigen, and generally occurs in younger people. Intrinsic asthma caused by upper respiratory infection, exercise, emotional instability, cold weather, the change of humidity occurs in adult patients.
According to the aspect of pathophysiology, asthma has been recognized as a chronic inflammation occurred by following procedure; Inflammatory cells are proliferated, differentiated, and activated caused by cytokines reproducing in T-helper 2 immune cells and is moved to air way or neighboring tissue thereof. The activated inflammatory cells such as neutrophil, mast cell etc release a variety of inflammatory mediators, such as cytokines, chemokines, signaling molecules, adhesion molecules and growth factors and the structural cells in airways are involved in various stages of asthma (Elias J A et al., J Clin Invest., 111, pp 291-7, 2003). In numerous studies using knockout mice models and clinical research, the critical observations in asthma could fall into several characteristic parameters, such as immune responses, eosinophilia, AHR and structural remodeling (Moffatt J D. Pharmacol Ther, 107, pp 343-57, 2005; Spina D et al., Trends Pharmacol Sci, 23, pp 311-5, 2002). Each of the parameters seems not to have direct correlations with one another; however, IgE-mediated immune response and eosinophilia are prominent symptoms in the airways of allergic asthma (Bochner B. S. et al., Annu. Rev. Immunol., 12, pp 295-335, 1994; Bousquet J et al., N. Engl. J. Med., 323, pp 1033-9, 1990), and the produced cytokines such as IL-4, IL-5 and IL-13 in the allergic process also play an important role in AHR development and airway remodeling (Riffo-Vasquez Y et al., Pharmacol. Ther., 94, pp 185-211, 2002). Indeed, asthma is a result of orchestrated inflammatory events, many of which involve specific inhibitors acting on the pathway of asthma, for example, histamine H1 antagonists, thromboxane antagonists, platelet-activating-factor antagonists, cyclooxygenase inhibitors, nitrogen monooxygenase inhibitors and prostaglandin inhibitors, have been tried but have failed in clinical trials (Moffatt J. D., Pharmacol. Ther., 107, pp 343-57, 2005). In contrast, glucocorticoids, which suppress the progenitor levels of inflammatory cells to baseline by widespread inhibition of cytokine synthesis and cytokine mediated immune-cell survival, has been used to manage the symptoms of asthmatic patients over a period of 30 years as far (Baatjes A. J. et al., Pharmacol, Ther., 95, pp 63-72, 2002). These reports suggest that the therapeutic approach for asthma management should focus on restoring the balance of asthmatic parameters rather than searching for potent inhibitors of specific pathways of the asthmatic process.
Tiarella polyphylla D. Don (Saxifragaceae) is a single species belonged to the genus in Korea. It inhabits in South-West in China but only on the summit of Ullung Island in Korea. Previously, it has been isolated tiarellic acid with corosolic acid, tormentic acid and so on (Park et al., Arch Pharm Res., 25, pp 57-60, 2002), and others reported an inhibitory effect on the expression of MMP-1 and type 1 procollagen in UV-irradiated skin fibroblasts (Moon et al., J Ethnopharmacol., 98, pp 185-189, 2005).
However, there has been not reported or disclosed about the suppressive effect on inflammatory, allergic and asthmatic disease of the extract of Tiarella polyphylla and tiarellic acid isolated therefrom in any of above cited literatures, the disclosures of which are incorporated herein by reference.
Accordingly, the present inventors have discovered that the extract of Tiarella polyphylla and tiarellic acid isolated therefrom show the inhibitory effect of tiarellic acid against LTC4 release in vitro and the suppressive effect on the IgE level and the cytokine (IL-4, IL-5 and IL-13) production, airway hyperresponsiveness, and leukocyte infiltration in OVA-induced asthmatic mice for the expectiation of contribution to asthma management.